The overall goal of this project is to develop an experimental and theoretical framework enabling mechanistic understanding and quantitative prediction of the influence of ingested lipids on orally delivered compound absorption. Lipids, in the form of food or drug delivery vehicles, can enhance oral absorption of some compounds several hundred percent; however, lipids can also cause several-fold decreases in absorption, or have no effect. These effects are not currently amenable to quantitative prediction, yet hold tremendous significance with respect to drug delivery, nutrition, and food-related diseases, including obesity. While previous studies have probed specific aspects of lipid function in the gastrointestinal (GI) tract, it is proposed that an integrated, systems based approach considering multiple parallel, dynamic processes (compound dissolution, lipid digestion, partitioning into colloidal phases, absorption) will enable quantitative understanding and prediction. While it is recognized that lipid digestion and absorption are highly variable, complex processes impossible to capture in their entirety in limited studies and modeling in a single project, the proposed approach is to develop an experimental and theoretical framework through comprehensive physical and chemical study and modeling of a controlled dynamic biorelevant in vitro system coupled with analysis of the inherently variable in vivo lipid digestio system. In the first aim, kinetics of digestion and associated dynamic structural (light scattering cryo-transmission electron microscopy (TEM), small angle x-ray and neutron scattering (SAXS and SANS)), and chemical (high performance thin layer chromatography with mass spectrometry (HPLC/MS)) features of colloidal species will be characterized in vitro and in vivo. In the second aim, the influence of lipid digestion on kinetics of compound dissolution and partitioning into colloidal phases, characterized using electron paramagnetic resonance (EPR), will be studied using statistically selected compounds representing broad ranges of physicochemical properties. In the third aim, the influence of lipids on intestinal membrane permeability (paracellular and transcellular) and drug absorption, considering passive and carrier-mediated as well as both portal and lymphatic routes, will be studied in vitro and in vivo. In the fourth aim, quantitative mathematical expressions developed in the first three aims to describe kinetics of key processes (dissolution, partitioning, digestion, absorption) will be integrated into a systems-based mass balance model to ultimately predict the influence of lipids on rate of overall oral absorption and bioavailability. The research team embodies the multidisciplinary expertise necessary to transform fundamental knowledge of lipid digestion to quantitative prediction: a chemical engineer with experimental and modeling expertise in lipid- based oral drug delivery, a physicist with expertise in structural characterization of lipid-based colloidal systems, a medical doctor with expertise in lipid digestion biochemical analysis, a chemist with expertise in EPR studies of microenvironment, and a pharmaceutical scientist with expertise in pharmacokinetic studies.